Synthesis of thiazolidinediones has been described in EP 177 353. Namely the preparation of compounds of formula VII wherein B is an oxygen or sulfur atom, R2 is an alkyl, acyl or hydroxyalkyl, is described by reacting of a compound of formula VIII wherein X is a halogen,and a phenolthiazolidinedione of formula VI 
The reactions are carried out in alkaline environment in organic solvents (e.g., dimethylformamide).
The method as described in EP 177 353 cannot be simply used for the synthesis of pioglitazone since in reacting 5-ethyl-2-pyridyl-ethylhalide with an appropriate phenol in an alkaline medium elimination reaction resulting in vinyl pyridine will prevail.
Therefore EP 193 256 discloses another reaction, which can be described by the following scheme 
A major drawback of this method is non-standard course of the reduction of the nitro group on palladium (reaction time is 3 hours up to several days), which is apparently dependent on the contents of impurities in the starting compound and in the solvent. The impurities apparently cause poisoning of the catalyst; therefore additional catalyst has to be gradually added. Longer reaction time results in formation of larger amounts of impurities and lower yields.
Further methods how to solve this problem have been elaborated in EP 257 78 1, in Chem. Pharm. Bull. 39(6) 1440–1445 (1991) and in EP 506 273 and EP 816 340. A common feature of all these methods is the reaction of a compound of formula III wherein Z is a leaving group of general formula R3SO3 wherein R3 is an alkyl or aryl, with an alkali metal p-hydroxybenzaldehyde or p-formylphenolate, i.e. with a compound of general formula IX wherein M can represent an alkali metal or hydrogen.
The product of formula X further reacts with thiazolidinedione yielding a benzylidene compound of formula XI which is converted to pioglitazone (formula I) by reducing on palladium.
The methods in the above-cited patents differ especially in the media in which reaction of the compound IX with the compound III is carried out. In EP 257 781 and in Chem. Pharm. Bull. 39(6) 1440–1445 (1991) reactions in a heterogeneous environment methylene chloride-water in the presence of a phase transfer catalyst have been described. In this embodiment, the main problem lies in the phase transfer. In the embodiment according to EP 506 273 an alkali metal 4-formylphenolate was first isolated and used as the starting material in the subsequent steps of the preparation. The reaction occurred in an anhydrous environment, preferably in ethanol. In EP 816 340 reaction in an anhydrous solvent mixture containing a low-molecular alcohol with another organic solvent (for example toluene) is described.
A drawback of the above-described methods is necessity of pressure reduction of the double bond of compound XI, i.e. 5-(4-(2-(5-ethyl-2-pyridyl)ethoxy)benzylidene)-2,4-thiazolidinedione. The following methods are known:                According to EP 257 781 reduction is carried out with hydrogen under catalysis with rather expensive palladium at the gauge pressure of 50 kg/cm2 and the temperature of 50° C. with the yield of 64%.        According to EP 506 273 at the gauge pressure of 100 kg/cm2 and the temperature of 110° C. the yield is 72%. Higher yields can be obtained at the expense of increasing the pressure, which entails higher demands for safety of the reaction. Higher temperatures bring about generally higher risk of formation of undesired products.        An attempt at solving these problems has been given in the patent application WO 93/13095. It relates to reduction with sodium tetrahydroborate catalysed with cobalt chloride.        